JPS59216893A - Organogermanium compound and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (A is H, methyl, ethyl; B is H, methyl, ethyl, phenyl; Y is hydroxy, halogen, amino; Z is halogen, oxygen atom which bonds with another atom). EXAMPLE:2-Methyl-3-(trichlorogermyl)butanoic acid. USE:Hypotensor, antitumor agent. PREPARATION:For example, a trihalogermylpropionic acid derivative resultant from addition reaction of a trihalogermanium represented by the formula: HGe X3 (X is halogen) to an acrylic acid derivative of formula II is chlorinated with a chlorinating agent such as thionyl chloride to form a trihalochloride. Then, the product is allowed to react with, in turn, ammonia and hydrogen chloride to form a trihaloamide compound of formula IV, which is hydrolyzed to give the objective compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an organic germanium compound and a method for producing the same.

Germanium (Ge), which is a homolog of carbon, and silicon (
Si) has been the subject of research in the fields of physics and inorganic chemistry for many years due to its unique property of having a semiconductor effect, but in recent years, research on its organic derivatives has been actively conducted. , and the results of this research have also been published.

Among them, research on organic germanium compounds has made remarkable progress.For example, carboxyethyl is a macromolecular compound whose basic skeleton is a germanium propionic acid derivative, and in which the basic skeleton is linked in countless ways by alternately bonding its germanium atoms and oxygen atoms. Germanium sesquioxide (compound a) has attracted widespread attention in pharmaceutical and medical societies since it was revealed that while it exhibits extremely strong antihypertensive and antitumor effects, it has no side effects at all. As represented by , it constitutes a new and interesting research field.

In addition, based on the above facts, further experiments on organic germanium compounds revealed that a macromolecular compound (7) which is a cinnamic acid amide derivative of germanium and has a germanium-oxygen bond similar to that of compound a above. It has been found that yloxyethylphenylgermanium sesquioxide (compound b) is an extremely useful compound that exhibits physiological activity comparable to that of compound a at a lower dose than compound a.

The applicant for the patent of the present invention and related research groups have published research on many organic germanium compounds, including the two types of compounds a and b mentioned above, but the mechanism of physiological activity exhibited by the sesquioxides is unclear. To date, it has not been clearly elucidated, and some researchers have proposed the theory that the activity originates from the germanium-oxygen bond formed in the compound. In other words, it can be said that the physiological activity of organogermanium compounds tends not to be explained by the concept of structure-activity relationship, which is well known in Japan. Even if the structure is similar to the known one,
It is thought that there are substances that exhibit excellent physiological activity.

Thus, organic germanium compounds such as compounds a and h are generally obtained by hydrolyzing the corresponding trichlorogermanium compound.

Compound a can also be obtained by the same process, but there are some points that should be improved in this production method.

That is, substituted acrylic acid amide represented by cinnamic acid amide (■) in the above formula and substituted acrylic acid chloride that can be easily converted thereto are generally extremely expensive compared to unsubstituted acrylic acid derivatives, or At present, most of them are difficult to obtain, which poses a major obstacle to synthesis.

Incidentally, if the price of unsubstituted acrylic acid and acrylic acid amide is set as 1, then the prices of substituted acrylic acid and its amides are as shown in the following table (- indicates those that are difficult to obtain). show).

Furthermore, even if a substituted acrylic acid compound such as the cinnamic acid amide is obtained or synthesized from substituted acrylic acid as a raw material, the addition reaction between the substituted acrylic acid amide and a trihalogermane such as trichlorogermane is generally not possible. +X, Ge C-C-C0NH'+-n tends to form, and the fatal problem of poor yield of pure adducts cannot be overcome.

In view of the above-mentioned circumstances, the present invention was made with the object of providing an organic germanium compound with a novel structure that has excellent physiological activity similar to conventionally known organic germanium compounds, and a manufacturing method that does not have disadvantages in terms of economy and reactivity. 1 The organogermanium compound of the present invention has a general formula (wherein one is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, and B is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, or This organic germanium compound is characterized by being represented by a phenyl group, Y is a hydroxyl group, a halogen group, or a ryomino group, and Z is a halogen group or an oxygen atom shared with others. (In the formula, A is a hydrogen atom, 5B is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, or a phenyl group, respectively.) IJ/) Rogelman HGe X3
111 (wherein X represents a halogen group) 6 and the resulting trihalogenylpropionic acid derivative represented by the general formula:
The trihalochloride represented by the general formula is obtained by chlorination with a chlorinating agent such as thionyl chloride, and the chloride (by treating Vl with ammonia and then hydrogen halide, the general formula
A or (in the formula, H is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, and B is a hydrogen atom or a methyl group). trihalogermane T (Ge A trihalogenylpropionic acid derivative represented by the general formula,
The trihalochloride represented by the general formula is obtained by chlorination with a chlorinating agent such as thionyl chloride, and the trihalochloride represented by the general formula is obtained by treating the chloride tv+ with ammonia or directly hydrolyzing with aqueous ammonia. Organic germanium prepared by the general formula % formula % [11 (wherein, Y represents a hydroxyl group, a halogen group, or an amino group, and Z represents a halogen group or an oxygen atom shared with others] without isolating the amide form. Compounds
It is obtained by a manufacturing method characterized by:

7 Next, the organic germanium compound of the present invention and the method for producing the same will be explained in detail.

The compound of the present invention is represented by the following general formula, and Z in formula 1 represents a halogen group such as chlorine or bromine, or an oxygen atom shared with another.
The compounds of the present invention can be roughly divided into two groups depending on the content.

That is, when Z is an oxygen atom shared with others.

The compounds of the present invention form a group represented by the general formula, where A is a hydrogen atom or a lower alkyl group such as a methyl group, ethyl group, or propyl group, and B is the same hydrogen atom or lower alkyl group as A, or In the substituted or unsubstituted phenyl group, A is bonded to the α-position and/or β-position of the oxygen functional group described below, and B is bonded to the β-position of the oxygen functional group. Further, since Y represents a hydroxyl group, a halogen group, or a terimino group, when Y is an amino group, this group includes, for example, 1 1 CII3 l o'' cH.

01 CH5CH.

2 This includes a series of compounds.

When we measure various spectral data of these compounds, we find that all physical properties such as single-element analysis values, nuclear magnetic resonance absorption (NMR) spectra, spectra such as infrared absorption (IR) spectra, and thermal behavior by differential thermal analysis are obtained. The chemical data well supports that the above compounds are represented by formulas (I'-1) to (1'-4), and therefore, the compounds of the present invention belonging to this group are macromolecular compounds having a germanium-oxygen bond. It has been confirmed that there is, and to give an example, the above compound (1'-1), namely Oney
1 (')] CF(.

The result of elemental analysis is that the calculated value is Ge: self 9.75
.

C:26.30. )]: 4.41, N near, 63, while the measured value is Oe: 39.52. C:26.11,
T (:4.411, N near, 53 (each weight%), and in the IR spectrum it is 1655"-" (C=O
), 90 Qσ-' and 800crn-' (Ge-
The differential thermal absorption analysis (T)TA) spectrum shows an endothermic peak at 246°C and an exothermic peak at 315°C.

On the other hand, when Z in the general formula (11) is a halogen group such as chlorine or bromine, the compound of the present invention forms a group represented by the general formula (X represents a halogen group), where Substituents A and B are the substituents A and B in the above general formula fl'H.
Similarly, substituent A is bonded to the α-position and/or β-position of the oxygen functional group, and substituent B is bonded to the β-position.

Since the substituent Y represents a hydroxyl group, a halogen group, or an amino group, when the substituent Y is a hydroxyl group, it is included in this group.

ClCH3CH.

2 When a compound having a carboxylic acid as an oxygen functional group such as Cl is included, and the substituent Y is a halogen group,
- When a compound having an acid chloride as an oxygen functional group such as Cl Cl is included, and the substituent Y is an amino group.

C,jICH3 C4!　　　CI(.

C) CHs Compounds having amide as an oxygen functional group such as CHs will be included.

Similar to the compounds in the above-mentioned groups, the compounds belonging to this group were subjected to various instrumental analyzes and all physicochemical data such as single-element analysis values, NMR spectra, and II'L spectra showed that the above compounds had the formula (T' -1
) to (T'-12).1 For example, in the analysis (MS) spectrum of compound (I-1) (7)', m/e
A molecular ion peak was observed at =280, and in the ■R spectrum, 1690+c+n- heavy (C=O), 1
26 DCm-' (C-0), 395cm-" (G
e-C)), in the NMR spectrum "]';! +N
1.62(Ill, S, -Co)H')Ic'
F:t'L sotL absorption is observed, and in the M8 spectrum of compound (1'-7) CI, the molecular ion peak is Hg at mr/e = 298, and in the IFL spectrum, teeth.

1785cm-' (C=O), 920■'(c-
o), 40 Q cm-''(Ge-C)), and furthermore, compound (1'-11) j C no G e CHCHCON H2 I 1 C no cH,CH.

In the M8 spectrum of , a molecular ion peak was observed at m/e = 279, and in the IR spectrum.

6 absorption is seen at 1655 cm-' (C=O), 42[], and 410 (both Ge-CJ).

Next, the method for producing the compound of the present invention as described above,
The following steps will be explained one by one.

TIII flVI (%TI
111 That is, the first step of converting the acrylic acid derivative represented by the general formula +ITI into trihalogenylpropionic acid IVI represented by the general formula (1v) is to convert the acrylic acid derivative f
This is a known addition reaction between ull and trihalogermane (II), and various reaction conditions are selected depending on the structure and reactivity of the acrylic acid derivative (II).
For example, an acrylic acid derivative (Tll) is suspended or dissolved in an inorganic or organic solvent such as hydrochloric acid or ether, and trichlorogermane is added dropwise at room temperature or under water cooling.

Alternatively, there is a method in which trichlorogermane is dissolved in concentrated hydrochloric acid, and then the acrylic acid derivative rlIl is added dropwise at room temperature or while cooling with water. When this is recrystallized from n-hexane etc., trihalogenylpropion e (
IVI is obtained with a yield of about 80-90%.

Next, the second step of converting the trihalogenylpropionic acid (TVI) obtained in the first step into a trihalochloride represented by the general formula (Vl) involves converting the hydroxyl group of the carboxylic acid using a chlorinating agent such as thionyl chloride. It is a chlorination reaction,
This process is also a general process in which trihalogermylpropionic acid + Ivl is dissolved in an appropriate solvent, or treated with an excess amount of thionyl chloride without a solvent, and after one reaction is completed, excess thionyl chloride is distilled off, and the residue is distilled under reduced pressure. The procedure can proceed with yields of about 55-90%.

still.

If economics can be ignored, the corresponding acrylic acid derivative fu
1 l of acid chloride may be obtained and strained in an organic solvent such as ethyl ether to add trichlorogermane.

Furthermore, the trihalochloride obtained in the above second step is expressed by the general formula f
The compound of the present invention represented by VTl (3-a to be converted)
The process consists of a substitution reaction of acid chloride to ryomide and a hydrolysis reaction of the halogen group bonded to germanium. Among these, the substitution reaction involves dissolving the trihalochloride in a solvent such as anhydrous benzene and drying the solution. After introducing ammonia, dry hydrogen chloride gas is blown in to ensure the germanium-halogen bond.
The yield of 11 is about 76-92%. Next, when this trihaloamide compound (VTI) is hydrolyzed, compound +Is is obtained, and this hydrolysis reaction is performed for compound a as described above.

As in the case of b, the trihaloamide compound (VD) may be poured into liquid water, stirred at room temperature or under heating for an appropriate period of time, and then two precipitated crystals may be collected.

Alternatively, the trihalochloride (Vl may be directly substituted with - of the compound of the present invention represented by the above general formula +1') instead of being isolated as the corresponding trihalamide and then hydrolyzed. That is, as in Step 5-b, after dissolving the trihalochloride TV) in a solvent such as anhydrous benzene, dry ammonia is introduced into this solution, water is further added, and after stirring, the compound (■ ), and the yield in this case is about 72-96%.

According to the above manufacturing method of the present invention, the general formula +I+
- of the present invention represented by - can be obtained using an extremely inexpensive and easily available unsubstituted acrylic acid derivative as a raw material, without using substituted acrylic acid derivatives that are generally extremely expensive or difficult to obtain. Therefore, the economic benefits that can be achieved are immeasurable, especially when the compound of the present invention is produced on a large scale.

In addition to being economical, the production method of the present invention does not use an amide of substituted acrylic acid, so 4X, GeC-C-C
By treating the trihalochloride with ammonia and then introducing hydrogen halide, it is possible to obtain a high-yield, high-purity trihaloamide without producing a polymer of 0NH-)-. , and even more.

By introducing water after treating the trihalochloride with ammonia, it is possible to obtain a compound represented by the general formula +15.
The compound of the present invention can be efficiently produced without isolating the compound (presumed to have a structure such as C-C-C0NH).

On the other hand, the compounds of the present invention obtained by the production method described above are all novel organic germanium compounds,
The substance represented by the general formula (1) exhibits excellent physiological activity and has a higher solubility than conventionally known compounds, and can improve its bioavailability. It is useful in that it can be used as an intermediate in producing the compound represented by 'l.

Next, an experimental example of the present invention will be described.

Experimental Example 1 Synthesis of trihalogenylpropionic acid■ Synthesis of compound (■“-1) (E)-2-methyl-2-butenoic acid 2[], 02f(0
, 2 mol) was dissolved in 100 al of dry ethyl ether.

Trichlorogermane under water cooling 36. After adding Of (0.2 mol) and stirring for 2 hours, the precipitated crystals were recrystallized from n-hexane to obtain 42.86 f of colorless plate-like crystals of the compound (U'-T"). The yield was as follows. It was 76.5%.

Compound (T-1) 2-methyl-3-(1-lichlorogermyl)butanoic acid Melting point 71.0-72°C Elemental analysis Calculated value Ge: 25.92 C: 21.4
4 H: 3.24C no 17.98 Experimental value Oe: 25.6! rC:21.53H
:3.26Cノ:3796 TR(KRr, cm-') 1690(C=(')
), 1260(C-0).

420.405,395(Ge-C)) NMR(δ,
(J)Cl3) 1.43(31-], d, fle-
('rf(-CH3).

1.44 (31-1, d, CH, -CH-C0)
260 (III, m, Ge-C).

K, 12 (III, m, CHq-CI-I
C0) 11, <52 (IH, s, flO(11-])
MS (m/e) 28rl (M),
285(M-C)), 144 ((1eC,,/2) ■ Synthesis of compound (1'-2) 3-Methylcrotonic acid 2n, Of! (0.2 mol) was suspended in 100mzI of concentrated hydrochloric acid. , hereinafter the compound (1'-
The colorless columnar crystals of compound (T'-2) were treated in the same manner as in 1) to give 46.75'? %is. The yield was 83.6%.

fHymonide (I'-2) 6.3-dimethyl-ro-(trichlorogermyl)butanoic acid Melting point 61-62°C Elemental analysis Calculated value OP: 25.92 C: 21.4
4 IT: 3.24C: 37.9B Experimental value Ge: 25.78 C: 21.55. H:3
．． 22C: 37.78 IR (KBr, cm) 1700 (C=O), 1
200(r-c)+415.400,380(Ge-C
)) NMR (CDC)3. δ) 1.50(6H,s,
-CH5).

2.76 (2H, s, -CH2-).

11.43 (IH, s, COCoo H) (m/e) 280 (M+), 24
5 (MC)).

179 (GeC), ), 144 (GeC), ) One compound (T-2) could also be synthesized using dry ethyl ether as a solvent.

■ Synthesis of compound (1'-3) After dissolving 29.6f (0.2 mol) of trans-cinnamic acid in dry ethyl ether, a trichlorogermane reaction was carried out in the same manner as in the case of compound (r'-i). Separate the precipitated crystals and recrystallize them from benzene-n-hexane (1:5) to obtain 6 colorless plate-like crystals of the 1H compound (T'-1).
1.59 i43. The yield was 93.8%.

Compound (n'-1 3-phenyl-3-(trichlorogermyl)propionic acid Melting point 83-84℃ Elemental analysis Calculation 4m', CJe: 22.12 C
:32.95 H:2.77Cj! : 32.41 Analysis value ne: 22.30 C: 32.85 T-
1:2.83(ゝ):5248 Ill(KBr, Cln-') 1710(C=0)
, 1600.1490(-CaHi) , 700(
C-H).

420.400 (Ge-C)) NMR (CDC), δ) 3.17 (2H, d
, -(H2-).

3.93 (III, t, Ge-C-14)
, 7.35 (5H,s, C6H5).

8.57 (I H, s, -COOTI) MS (
m/e) Ro2s (Ni), 293 (M-
C)) ■ Synthesis of compound (1-4) 32.4 f (0.2 mol) of α-methylcinnamic acid was dissolved in 300 g of dry ethyl ether and treated in the same manner as the above compound (I-1) to form the compound. 50 colorless plate-like crystals of (1-4)
．． I got 99. The yield was 74.4%.

Compound (r-4) 2-methyl-3-phenyl-3-(trichlorogermyl)propionic acid Melting point 91-92°C Elemental analysis Calculated value fle: 21.22 C: 35.
10 H: 3.24 C: 31.09 Analysis value Ge: 21.15 C: 35.05 H:
3.23C: 30.98 IR(KRr, cM-") 168r) (C=O).

1600.1490 (-Can5).

7[]0 (-<ge1).

425.405,590 (fle-C)) NMR (CI
') Cノ, δ) j, 46 (3H, d, -Crb
).

3.50 (IH, m, -CH-) 113.70 (1
'H, d, Ge-1pH-).

763 (511, m, -C6)1s).

9.63 (I n , s , -COOH) MS (
m/e) 542 (RJ+), 307 (M-
C)).

163 (MC,/!,).

179 (GeC), ).

144 (Ge-C),) Experimental Example 2 Synthesis of trihalochloride■ Synthesis of compound (T'-5) 3-(trichlorogermyl)butanoic acid 26.6f(0,
Add 100a/thionyl chloride to 1 mole),
After heating for 0 hours, excess thionyl chloride was distilled under reduced pressure to obtain compound (1-5) with a boiling point of 99-100°C.
24.72 was obtained as a colorless transparent fraction of 1/6 mm). The yield was 87%.

Compound (1-5) 3- () I+chlorgermyl)butyl chloride elemental analysis Calculated value Ge: 25.52 C: 16.89
H: 2.12 'C: 49.85 Experimental value Ge: 25.36 C: 16°61 H:
2.2IC no: 49.69 Refractive index etc. n: 1.5108 d,
1.66191) 20 TR, (KBr, m-') 1790 (C=0), 5
90 (Ge-C), 430.100 (Ge-C10 0 (Ge-C)) N, δ) 1.48 (3H, d, -CH
,).

2.72 (IH, m, Ge-CH).

3.28 (2H, m, -CHz) MS (m/e
) 284 (M”), 249 (M-c)).

179 (GeC), ).

105 (M-GeCJs) ■ Synthesis of compound (T'-6) 2-methyl-6-(trichlorogermyl)propionic acid 26.6 f (0.1 mol) was added to the above compound (I-5).
After treating with thionyl chloride and ride in the same manner as above, the mixture was subjected to vacuum distillation to obtain 25.19% of compound (1'-6) as a colorless transparent fraction with a boiling point of 101 to 1015°C. The yield was 88%.

Compound (1-6) 3-(trichlorogermyl)-2-methylpropionyl chloride Elemental analysis Calculated value Ge: 25.52 C: 16.8
9 H:2.12C:49.85 Experimental value Ge:25.41 C:16.87 H:2
．． 15CJ: 49.82 Refractive index, etc. n: 1.5074 d:
1.66221) 20 IR, (KBr, c+n-') 1790 (C=0),
95 (3 (C-0), 590 (Ge-C), 4.25,405 (Ge-C)) NMR, (CDC13, δ) 1.56 (l-1, d
, -CT(3).

2.83 (2H, m, Ge-CH2).

3.38(IH,m,-(j(-Co)MS(m/e)
284(M), 249(MC)).

105 (M-105(,).

179 (GeCj!3) The above compounds (1'-5) and (r'-6) can also be synthesized by adding trichlorogermane to the corresponding acrylic acid chloride. That is, for compound (+-5), crotonoyl chloride 2
0.99 (0.2 mol) in dry ethyl ether 20
Dissolved in Q me and diluted with trichlorogermane 36,0 under water cooling.
After adding 9 (0.2 mol) and stirring for 2 hours, the ethyl ether is distilled off and the residue is subjected to vacuum distillation.
Regarding compound (T-6), 20.91i' (0.2 mol) of methacryloyl chloride is similarly reacted with trichlorogermane and then subjected to vacuum distillation.
This method also yields the r compound (1-
5) and (1-<S) were obtained in yields of 72% and 54.3%, respectively.

■ Synthesis of compound (I'-7) 3-(trichlorogermyl)-2-methylbutanoic acid 2B
, Of (0.1 mol) was treated with thionyl chloride in the same manner as the above compound (I-5), and then distilled under reduced pressure to obtain compound (II'-7) with a boiling point of 99-100°C/6 my
2702 was obtained as a pale yellow fraction of 1-12. Yield is 9
It was 0.4%.

Compound f (T-7) Self-(trichlorogermyl)-2-methylbutanoic acid chloride Elemental analysis Calculated value ()e: 24.32 C: 20.
12 H: 2.7 DC saw 4750 Experimental value Ge: 24.41 C: 20.03 H:
2.84C: 47.41 Refractive index, etc. n: 1.51n5 d:
1.60795D 20 IUL (K11r, c+++ power 1785 (C'=0)
, 920 (CO).

5so(ne-c).

480.400(Ge-C)) NMl'L(C'l'1)C4! , , δ) 1.45
(3T-1, d, Ge-CH2-CH3).

1.58 (314, d, CTCs-CH-C0
).

2.70 (IH, m, Ge-C) (-).

3.28 (IH, m, -CH-Co)MS (m/e)
29B(M), 263(MC)).

179 (()eCノ), 144(GeC),).

119 (M-GeC), ) ■ Synthesis of compound (1″-8) 3-(trichlorogermyl)-3-methylbutanoic acid 2a
After treating Of (0.1 mol) with thionyl chloride in the same manner as the above compound (1'-5), it was subjected to vacuum distillation to give compound (T'-8) as a pale yellow distillate with a boiling point of 90°C and 15% nt. 25.55' was obtained as a minute. The yield was 85.5%.

Compound (1-1 3-(trichlorogermyl)-3-methylbutanoic acid chloride elemental analysis Calculated value Ge: 24.32 C: 20.1
2 H:2.70 ('4:47.50 Analysis value Qe:24.53 C:1995 H:2
．． 68C): 47.26 Refractive index, etc. n: j, 5114 d:
1.5968D 211
1R (KBr, cm-') 1800 (C=O)
, 595 (()e-C).

430.400 (Ge-C,j-NMR (CDCl2.δ) 1.50 (3FT
, lI, Ge-C-(Jj3).

5.52 (2H, s, -CH2-Co) MS (
m/e) 29B (M”), 179 (GeC),
).

119(M-GeC), ) 2 Experimental Example 3 Sesquioxide type compound (r'-i) ~
Synthesis of (T'-4) 3-1 Method via trihaloamide ■ Synthesis of r compound (1'-1) i'r, 3-(trichlorogermyl)-buty acid chloride 5.691 (0 , 02 mol) in anhydrous benzene 15
0++t/, water-cooled waning ammonia was introduced for 1 hour, dry salt 1 arsenic gas was introduced for 1 hour, then acetic acid methyl ester in Ome was added, stirred and filtered, and the P solution was distilled. After leaving, the residue was dissolved in acetone-benzene (
1:2) to obtain 52 (94.5% yield) colorless needle-like crystals of compound f (T″-91) having the following first-order characteristics.

Compound (1-9) 3-(1-lichlorogermyl)butanoic acid amide Melting point 126-124°C Elemental analysis Calculated value Qe: 2739 C: 1813
H:3.04Ctt:an12 N:5.2B Actual value Ge:2760 C:'18.13 F(
:3.08C):4[1118N:5.25 TR(KBr, crn-')345[1,3350,3
300, 3250 (N (]), 1665 (C=0),
60[1(Ge-C), 420,! +80(Ge-(
1) MS (m/s) 265 (M+), 230 (M-C4)
Compound (1-9) obtained by straining in this way was 5.70
Using f (0.02 mol), how can only the germanium chlorine bond be prepared using the conventional method? By hydrolysis, 2.9f of compound (T'-1) having the following characteristics was obtained. The yield was 798%.

Compound (r'-1) 2-carbamoylethylgermanium sesquioxide elemental analysis Calculated value Ge: 39.73 C: 26.3
0 H: 4.41N near, 67 Experimental value (')e: 39.60 C: 26.15
H: 4.4ON near, 51 1R, (KBr, em-”) 1”655 (CmO)
, 900.800 (Ge-0) T) TA Endothermic peak 348.
Exothermic peak Q) at 410°C.
5.69 r (n, [12 mol) of 2-methylpropionic acid chloride (+・11 chlorgermyl) with ammonia and salt f arsenic gas in the same manner as in the case of the above compound (I'-1). After the reaction, post-treatment was performed to obtain colorless plate-like crystals of the compound (1'-10) having a first-order ff 'Cj characteristic at -4,66! i' (8B, r1% yield) is obtained.

Compound (1-10) 3-(trichlorogermyl)-2-mer-propionic acid amide Melting point 114-115°C Elemental analysis 8' Calculation: 27.39
C: 18.13 )]: 3.04 C: 4n, 12
N: 528 Experimental value Oe: 27.71 C: 18.23 H: 3. D
7Cffl: 4n, n6 N: 5.20IR (KRr
, c+n-') 345[], ro350.3270.
3230 (N-■1), 1660 (CmO).

6 [10(()e-C), 415 (fle-CJ
) 'N'N4R(dioxan-d6.δ)1
．． 34 (311, d, -(Jla').

2.20 (2TI, m, Ge-C112-) 5 2.90 (IH, m, flT-T-Co) MS (m/
e) 265 (M+), 23rl (M-
C)) Then this f compound (T"-10) was added to 5.70
By using f (0.02 mol) and hydrolyzing in the same conventional manner as above, a compound having the following characteristics (
1'-2) to 3.01? (%) The yield was 82%.

After compounding + (T'-2) 2-carbamoyl-2-methylethylgermanium sesquioxide elemental analysis: [Calculated value Ge: 39.73 C: 26.
30 H: 4.41N near, 67 Experimental value Ge: 59.52 C: 26.37 r
(:4.39N=761 1R(KBr, Cm-') 1660(CmO), 9
00,800 (Ge-0) DTA Endothermic peak at 246℃ '515℃
Exothermic/peak ■ Synthesis of Compound (1'-3) First, 5.8 f (0.02 mol) of 2-methyl-6-(trichlorogermyl)butanoic acid chloride was added to the compound (1'-1''). In the case of 1, colorless columnar crystals of compound (T'-11) having the following characteristics were reacted with ammonia and hydrogen chloride gas in the same manner as Yoshi, and then post-treated.
．． Obtain 1F (76.0% yield).

Compound (T-11) 2-Methyl-6-(trichlorogermyl)butanoic acid amide Key point 141-142°C Elemental analysis Calculated value Ge: 26. [11C:21.52
1-1:361C/:3811N:5.03 Experimental value Ge:25.93C:21.49H:
'! =, 65C):”) 7.96 N: 4.9B IR (KFlr, cIn-') 3450, 32
70. Ro2111 (NH).

1655 (CmO), 605 (Ge-C).

420.410(Ge-C)) NMR(acetnn-d6.δ) 1.30 (
3H, d, (le-CH-CT(3).

1.44 (3H, d, CIT, -CI(-Co)
.

2.52 (IH, m, 0e-CI-1).

3.22 (IH, m, -CH-Co) MS (m/e) 279 (M+), 244 (M-C
J).

179 (GeCJts), 144 (GeC4) Then, this compound (■“-11) was converted to 5.97 f(0,
A compound (T'-3
) was obtained at 3.15F. The yield was 80%.

1H compound (1,'-3) 1,2-dimethyl-2-carbamoylethylgermanium sesquioxide elemental analysis Calculated value ne: 66.90 C: 50.5
3 H: 5.12N near, 12 Experimental value Ge: 36.59 C: 30.47 H:
5.05N Near, 05 IR (KBr, cIn-') 1660 (C=O).

895.795 (Ge-0) DTA Endothermic peak at 62,432°C.

Exothermic peak at 307°C NMR (D, O, δ) 1,25 (3HedyGe-
CM-Csu,).

1.55(3)1. d,C)(,-(Jl-CO).

2.90 (2H, m, CH-CH) ■ Synthesis of compound % (T'-4) First, 5.97 t (0.02 mol) of 3-no-1-ru-3-(trichlorogermyl)butanoic acid chloride )of,
In the case of the above compound t'/I(]'-1), ammonia and [f? , 7. React with the raw gas and then post-process.

5. Colorless prismatic crystals of compound (r-12) having the following characteristics. Of (92.2% yield) is obtained.

Compound (1-12) Ro-methyl-3-(trichlorogermyl)butanoic acid Absolute peak point 155-156"C Elemental analysis Total 'tA-iFi Ge: 26.OI
C: 21.52 H: 3.61 Cffl: 3811
N: 5.02 Experiment 1st shift Ge: 26.06 C: 21.41 H
:3.58Cノ:37.97 N14.95 NMR (ace tone-d6, δ) 1.38
(6H, s, -CH5), 2.80 (2)(, s
, CH2') MS (mle) 279 (M
), 244 (M-C, jri.

179 (neC]s), 14 d (GeC),)
Next, this compound? +(1-12) to 5.97t(0
, 02 mol) and hydrolyzed in the same conventional manner as above, a compound (T'-
4') was obtained at 2.99. The yield was 76%.

Compound (T'-4) 1.1-dimethylethylgermanium sesquioxide elemental analysis Calculated value Ge: 36.9D C: 30.5
3 H: 5.12N near, 12 Experimental value Ge: 36.49 C: 30j13 H:
5.12N near, DO IR, (KBr, σ-') 1665 (C=O),
890 (Ge-0) NMR (D20) 1.15
(6H,s, C-(C-view,)2), 2.48(2
H, s, CH2) I) TA Endothermic peak at 200, 240, 276°C 325°C exothermic peak 3-2) Direct synthesis method from IJ halochloride Q
flZ synthesis el(T”-5) (3-trilorylbutanoic acid chloride) 5.7Of(0,
02 mol) in 150 ml of anhydrous benzene, cooled with water and introduced dry ammonia for 1 hour, added 5 ml of water, stirred, separated the aqueous layer, and filtered with Gel Y filtration (Seifrodex 25
[Product Name]) and evaporated the P solution to dryness to obtain 2.65 f of colorless amorphous crystals. The yield was 72.4%.

This reaction was also carried out for compounds (+'-6) to (1'-8), and colorless amorphous crystals were obtained from each of them as shown in the table below. '-1) to (T'-4).

■ Also, the above compound 1 (1'-5) to (1'-'8)
was dissolved in a 14% NH,OH solution (40+t/ml), the precipitated crystals were collected, and the crystals were filtered through gel filtration (Serifidex 2).
5 [Part name]), the P solution was evaporated to dryness, and the compounds (1'-1) to (1'-4) were obtained in exactly the same manner. In addition, the yield etc. are shown in the table below.

Table 3 Examples In order to examine the in vivo usability of the sesquioxide type compounds obtained in Experimental Example 3, the solubility of these compounds in water at 25°C was investigated. compared to similar compounds.

It was found to have good water solubility as shown in the table below.

Table of Examples According to the method shown in Experimental Example 3 above, it is also possible to synthesize an organic germanium compound represented by formula 1.

That is, compound (1'-5) is obtained by treating the compound (1-3) with thionyl chloride and distilling it under reduced pressure to obtain a trihalochloride represented by the formula, which is then treated with ammonia in anhydrous benzene under water cooling. Will it react with gas?

Alternatively, it can be dissolved in a NH,011 solution and then brought into contact with water; the yield in this case was 86.2% in the former case and 755% in the latter case.

For reference, the physical properties of compounds (1'-13) and (T'-5) are shown.

Compound (1-13) Boiling point 14B-149℃/4mvnH? elemental analysis
Calculated values Ge: 2094 C: 31.19 H: 2.
33CJ: 4092 Experimental value Ge: 20.76 C: 31.08 H: 2
．． 49Cj! :40.90 Refractive index etc. n :1.573(S d
: 1.5793D
20TR (KBr, cIn-”) 1795 (C
=(')).

7110((3+-H), 425,4.[lO(G
e-CI) NMR, (CI)CI3. δ) 3.70 (2H,
dd, -CH, -Co), 3.92 (IH,, t, G
e-CH).

736 (5H, m, -C6H5) Compound (1'-5) Elemental analysis Calculated value Qe: 29.66 C: 44.1
6 H: 4.12 N: 5.72 Experimental value fle: 29.68 C: 43.82 H
:4.01N:5.66 IR1660 (C=o).

930, R95,8nO (Ge-0) DTA Endothermic peak at 252℃.

307. Physiological activity of rb compound produced by the method of the present invention at 400°C Experimental example 6: 8 CDFI mice (9 weeks old female) per group, 12 mice in the control group only. 1 x 10 IMC lung tumor cells 1
After 6 subcutaneous inoculations, 24 hours later, the compound (+'-5) was administered once a day at a dose of 25 Y/Kq and 5q/Kf was administered with 05% carboxymethyl cellulose for one day. The cycle of administering again for 6 days, taking a day off, and administering again for 6 days was repeated, and two days after the final administration, the tumor was dissected and the weight of the tumor was measured. The results are shown in the table below, and the compound (
I'-5) was found to exhibit particularly remarkable antitumor activity.

Table (Suppression of growth of IMCMC carcinoma type tumor) Representative Yoshikuni Koizumi

Claims (1)

[Claims] 1. General formula (wherein A is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, B is a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, or a phenyl group, Y is a hydroxyl group, a halogen group, or an amino group, and Z is a halogen group or an oxygen atom shared with others. C= C-C0OHtill (In the formula, A represents a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, and B represents a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, or a phenyl group, respectively. ) to the acrylic acid derivative represented by trihalogermanane HGeX3
(in the formula, X represents a halogen group), and the resulting trihalogenylpropionic acid derivative represented by the general formula,
The compound is chlorinated with a chlorinating agent such as thionyl chloride to form a trihalochloride represented by the general formula B, and the chloride [Vl is treated with ammonia and then hydrogen halide to form a trihaloamide form represented by the general formula, which is then hydrolyzed. An organic germanium compound represented by the general formula (wherein Y is a hydroxyl group, a halogen group, or an amino group; Z represents a halogen group or an oxygen atom shared with another) Production method. 3゜(In the formula, A represents a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, and B represents a hydrogen atom, a lower alkyl group such as a methyl group or an ethyl group, or a phenyl group, respectively.) , trihalogermanane HGe Xs
flll (in the formula, X represents a halogen group), and the resulting trihalogenylpropionic acid derivative represented by the general formula,
The trihalochloride represented by the general formula is obtained by chlorination with a chlorinating agent such as thionyl chloride, and the chloride (Vl is treated with ammonia or directly hydrolyzed with aqueous ammonia to form a trihalochloride represented by the general formula Without isolating the trihaloamide compound, the organic germanium compound is formed by the general formula (wherein, Y represents a hydroxyl group, a halogen group, or an amine group, and Z represents a halogen group or an oxygen atom shared with others). A method for producing an organic germanium compound characterized by: